title: Tissue plasminogen activator is required for the development of fetal alcohol syndrome in mice.
abstract: Ethanol exposure during developmental synaptogenesis can lead to brain defects referred to as fetal alcohol syndrome (FAS), which can include mental health problems such as cognitive deficits and mental retardation. In FAS, widespread neuronal death and brain mass loss precedes behavioral and cognitive impairments in adulthood. Because tissue plasminogen activator (tPA) has been implicated in neurodegeneration, we examined whether it mediates FAS. Neonatal WT and tPA-/- mice were injected with ethanol to mimic FAS in humans. In WT mice, ethanol elicited caspase-3 activation, significant forebrain neurodegeneration, and decreased contextual fear conditioning in adults. However, tPA-deficient mice were protected from these neurotoxicities, and this protection could be abrogated by exogenous tPA. Selective pharmacological modulators of NMDA and GABAA receptor pathways revealed that the effects of tPA were mediated by the NR2B subunit of the NMDA receptor. This study identifies tPA as a critical signaling component in FAS.
authors.affiliation: Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Noel
authors.forename: Erin H
authors.initials: EH
authors.lastname: Norris
authors.forename: Sidney
authors.initials: S
authors.lastname: Strickland
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000009:adverse effects / Q000494:pharmacology; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism; D000431:Ethanol / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D002492:Central Nervous System Depressants; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D010959:Tissue Plasminogen Activator; C505409:Casp3 protein, mouse; D053148:Caspase 3